MR:GR ratio is highest in hippocampal area CA2 These findings demonstrate a defining role for MRs in the acquisition of CA2 pyramidal neuron fate, maintenance of CA2’s molecular profile, and expression of CA2-dependent behaviors. Further, both widespread neuronal deletion and CA2-targeted deletion of MRs were sufficient to impair behaviors attributed to CA2 function. Unexpectedly, we found that MR deletion resulted in a complete loss of CA2 molecular identity all currently known molecular identifiers of CA2 drastically decreased in expression following deletion of MRs. In this study, we set out to investigate whether deletion of MRs affects CA2 neuron physiology and function. Recent studies have demonstrated that CA2 PCs are important for social memory, aggression, spatial processing, and detection of novelty, behaviors that have also been linked to MRs. CA2 pyramidal cells are further distinguished from neighboring CA1 and CA3 PCs in that they exhibit a unique pattern of gene expression that permits tight regulation of synaptic plasticity at CA3 → CA2 Schaffer collateral synapses and confers sensitivity to the social neuropeptides oxytocin and vasopressin, which may play a role in social recognition memory and aggression in mice. Although multiple reports have demonstrated that MR expression in the hippocampus is highest in area CA2, beginning embryonically and lasting through adulthood, the biological significance of this early and concentrated MR expression in CA2 neurons remains unknown. In the hippocampal Cornu Ammonis (CA) fields, MR protein and mRNA (Nr3c2) are both strongly expressed by pyramidal cells (PCs) during embryonic development and remain enriched in hippocampal PCs throughout perinatal life and into adulthood. Autoregulation of both MRs and GRs during this process, therefore, permits normal adaptations to stress. GR- and MR expression in hippocampal neurons is essential for normal regulation of the hypothalamic-pituitary-adrenal (HPA) axis, as GR- and MR-expressing neurons detect levels of circulating CORT and inhibit the HPA axis to terminate the stress response. GRs, on the other hand, are activated when an animal is stressed or during circadian periods when circulating CORT levels are naturally elevated. MRs have a tenfold higher affinity than GRs for CORT and are therefore thought to be occupied by ligand even under baseline, low-stress conditions. In contrast with GRs, which are expressed in virtually all cell types in the rodent brain, MRs are expressed primarily in neurons of limbic regions such as the hippocampus, lateral septum, and amygdala. Although both nuclear receptors recognize the same specific DNA promoter sequences called glucocorticoid response elements, GRs and MRs control distinct transcriptional networks, which regulate diverse functions in neurons, including apoptosis, differentiation, and survival. In most cells, including neurons, GRs and MRs act as transcription factors that control vast downstream networks of other transcriptional regulators, so activation of either receptor by the endogenous ligands cortisol or corticosterone (CORT) initiates complex programs of gene expression and repression. In the brain, glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) mediate learning and memory, emotional states, and behavioral and physiological responses to stress. Altogether, these results demonstrate an unappreciated role for MRs in controlling CA2 pyramidal cell identity and in facilitating CA2-dependent behaviors. We also found that CA2-targeted MR knockout was sufficient to disrupt social behavior and alter behavioral responses to novelty. Furthermore, embryonic deletion of MRs disrupted afferent inputs to CA2 and enabled synaptic potentiation of the normally LTP-resistant synaptic currents in CA2. Using three conditional knockout methods at different stages of development, we found a striking decrease in multiple molecular markers for CA2, an effect mimicked by chronic antagonism of MRs. Thus, we asked whether MRs regulate CA2 neuron properties and CA2-related behaviors. CA2 pyramidal neurons have a distinct molecular makeup resulting in a plasticity-resistant phenotype, distinguishing them from neurons in CA1 and CA3. Within the hippocampus, the highest expression of MRs is in area CA2. Mineralocorticoid receptors (MRs) in the brain play a role in learning and memory, neuronal differentiation, and regulation of the stress response.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |